Cardiovascular disease is a major cause of human morbidity and mortality in modern societies. Atherogenesis, the process by which vascular narrowings are formed, often results following vascular injury and is caused by the migration and subsequent proliferation of smooth muscle cells from the arterial media into the arterial intima of the afflicted vessels. Smooth muscle cell migration and proliferation are key events in the restenosis that occurs after angioplasty, atheroectomy, endarterectomy, and other similar procedures.
A major stimulus for smooth muscle cell migration and proliferation following vascular injury is believed to be platelet-derived growth factor (PDGF). PDGF is released from activated platelets at the site of vascular injury, whether the injury is due to mechanical, immune-mediated, or metabolic causes. PDGF can also be produced locally by activated macrophages, endothelial and smooth muscle cells. PDGF is a potent chemotactic agent and mitogen for both vascular smooth muscle cells and fibroblasts. Smooth muscle cells within proliferative lesions express many more receptors for PDGF than those cells residing within the normal vessel wall, suggesting that the cells which migrate to and proliferate within the lesion are selected for responsiveness to PDGF. PDGF acts by binding to and activating a specific cell surface receptor. The activated receptor then transmits signals to the cell cytoplasm and/or nucleus, thereby effectuating migration and proliferation.
New therapeutic treatment regimens are urgently needed for preventing or reversing the chronic and debilitating process of atherogenesis and related cardiovascular diseases. Compositions which block the binding of PDGF to its cellular receptor molecule, thereby preventing PDGF-induced cell migration and proliferation, may provide major therapeutic benefits for treating or preventing atherogenesis and may be useful in other related acute disease states. Ideally, the new agents will be potent, relatively non-immunogenic to most patients, easy to administer, stable in vitro and resistant to degradation in vivo, and economical to produce. Further, these agents should be capable of functioning at the earliest stages of smooth muscle cell migration and proliferation without interfering with long-term wound healing. The present invention fulfills these and other related needs.